Gut microbiota shapes the effects of saturated and polyunsaturated fatty acids on skin and hair follicle homeostasis.

High-fat diets are linked to obesity and skin and hair disorders, yet the role of specific lipid classes remains unclear. In this study, we show that cutaneous homeostasis is driven primarily by fatty acid (FA) composition rather than total fat content and is differentially regulated by the gut microbiota. Using omega-3 or omega-6/saturated FA-enriched diets under specific pathogen-free and germ-free conditions, we demonstrate that omega-6/saturated FA feeding promotes weight gain, dermal white adipose tissue expansion, sebaceous gland enlargement, and increased hair follicle proliferation. Systemic and adipose effects occur independently of the microbiota, whereas epithelial and follicular proliferation requires microbial presence. In contrast, omega-3 feeding limits adiposity and dermal white adipose tissue expansion regardless of microbial status but differentially regulates skin compartments in a microbiota-dependent manner. These effects are associated with selective microbiota-dependent regulation of circulating FAs: omega-6 species for omega-6/saturated FA feeding and omega-3 species for an omega-3 diet. Notably, circulating docosahexaenoic acid (22:6, ω-3) levels differ between specific pathogen-free and germ-free conditions in both diet groups, indicating microbiota-mediated control of systemic docosahexaenoic acid bioavailability. Together, these findings identify the gut microbiome as a selective regulator of FA metabolism and define a diet-microbiota-lipid axis that integrates systemic lipid availability with cutaneous homeostasis.